Coronaryheartdisease(CHD),leadingtomyocardialinfarction(MI)andpost-MIheartfailure(HF),isa majorcauseofmorbidityandmortalityintheUS.w?3-polyunsaturatedfattyacids,likeeicosapentaenoicacid (EPA),improveoutcomesinCHDandHF,butthisiscontroversial.First,severaltrialswithlow-dosew?3shave failed,butrecenttrialswithhigh-dosew?3s(REDUCE-IT,OMEGA-REMODEL)reportimprovedoutcomes. Second,themechanismofw?3-cardioprotectionisunclear,butfreefattyacidreceptor4(Ffar4),aGPCRfor long-chainfattyacids,isanovelmechanismtoexplainw?3-cardioprotection.Inmice,wewerethefirstto establishthatEPApreventscardiacfibrosisandcontractiledysfunctioninpressureoverload.Yet,EPAwasnot incorporatedintocardiacmyocytesorfibroblasts,thetraditionalmechanismforEPAcardioprotection. Alternatively,wefoundthatFfar4isexpressedintheheart,andFfar4incardiacfibroblastsinvitrowas sufficientandnecessarytopreventTGFb?1-inducedfibrosis.Thus,wehypothesizedthatEPA-Ffar4signalingis necessaryforEPAcardioprotection.However,weweresurprisedtofindthatFfar4alsohasw?3-independent effects.InmicewithsystemicdeletionofFfar4(Ffar4KO)onastandarddiet,wefoundthatTACworsens remodeling,butwithoutexaggeratedfibrosis,highlightingtheroleofFfar4incardiacmyocytes.Inmyocytes, wefoundthatFfar4wasnecessaryfortheexpressionofcardioprotectiveinflammatorygenesandactivationof phospholipaseA2(PLA2).Inhumans,wefoundthatFfar4expressionisdecreasedinhumanHF,andFfar4 polymorphismsareassociatedwithcontractiledysfunctioninFraminghamOffspring.Here,weproposeanovel paradigmwherefattyacidsfunctionassignalingmoleculestomaintaincardiachomeostasis.Wehypothesize thatincardiacmyocytes,Ffar4functionsasanw?3-independentcardioprotective,fattyacidnutrientsensor,and thatFfar4isnecessaryforEPAcardioprotection.Weproposefouraims.1)Todetermineifcardiacmyocyte Ffar4isnecessarytoprotectagainstischemia,cardiacmyocyte-specificFfar4KOmice(CM-Ffar4KO)willbe subjectedtoischemia-reperfusion(I/R)injury,andwehypothesizeworseoutcomesintheCM-Ffar4KO.2)To definecardioprotectiveFfar4signalingmechanisms,followingI/RinjuryinCM-Ffar4KOmiceandinhypoxiain culturedmyocytes,wewillmeasurecelldeath,inflammatorycytokines,PLA2-inducedoxylipins,andhowthis affectsmacrophagerecruitment.3)TodetermineifFfar4isnecessaryforEPAcardioprotection,CM-Ffar4KO onanEPA-dietwillbesubjectedtoI/Rinjury,andwehypothesizeEPAwillfailtoattenuateremodelinginthe CM-Ffar4KO.4)TodeterminethetherapeuticpotentialofFfar4,wild-typemicesubjectedtoI/Rinjurywill treatedwiththeFfar4agonistTUG-891post-MI.Inhumans,wewilltestforassociationsbetweenFfar4 polymorphismsandCVDinclinicalcohorts.AlthoughmorepatientssurviveMI,post-MIHFisrising.Here,we proposeFfar4as1)anovelcardioprotective,fattyacidnutrientsensor,2)apotentialtherapeutictargetto attenuatepost-MIremodeling,and3)themechanisticbasisforEPAcardioprotection.